GB2131020A - Bis(nitro-1-imidazolyl alkylamine) platinum complexes useful in radiotherapy or chemotherapy - Google Patents
Bis(nitro-1-imidazolyl alkylamine) platinum complexes useful in radiotherapy or chemotherapy Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
Abstract
Compounds of formula (I): <IMAGE> in which:- R1 represents a hydrogen or C1-C6 alkyl, R2 and R3 each independently represent hydrogen or C1-C6 alkyl, X represents a pharmaceutically acceptable ligand incapable of co- ordinating to platinum more strongly than does nitrogen of the moiety -NR2R3, a is 1 or 2, b is 0, 1 or 2, c is 1 or 2, d is 0, 1 or 2, e is 0, 1 or 2 provided that b+d is no greater than 2 and when d is greater than 0, e is greater than 0; are useful in increasing the sensitivity of tumor cells to radiation in radiotherapy and also in potentiating or enhancing damage to tumors by chemotherapeutic agents. Intermediates of the formulae <IMAGE> in which R2=R3=H, <IMAGE> are also claimed.
Description
SPECIFICATION
Improvements relating to compounds useful in radiotherapy or chemotherapy
This invention relates to compounds useful in the treatment of cancer patients by radiotherapy or chemotherapy, to a process for the production of such compounds, to formulations for administration and to methods of treating such patients.
Accordingly, the present invention comprises a compound of formula I
in which: R1 represents hydrogen, C,C6 alkyl,
R2 and R3 represent hydrogen or C1-C6 alkyl,
X represents a pharmaceutically acceptable ligand incapable of co-ordinating to platinum more strongly than does nitrogen of the moiety -NR2R3 aisi or2 bis0--2 cisi or2 dis0--2
eis0---2; provided that b+d are no greater than 2 and when d is greater than 0, e is greater than 0.
Pharmaceutically acceptable ligands X may be monodentate or form part of a bidentate ligand X2.
Although X preferably represents halogen and especially chlorine, the compound I may alternatively comprise a bidentate ligand of the formulaO.CO.CRaRbCO.O, for example, in which formula Ra and
Rb, which may be identical or different, each represent hydrogen or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group or CRaRb represents a cycloalkyl or cycloalkenyl group. Monodentate ligands X may be identical or different.
Although when X2 represents a bidentate ligand the configuration of the complex is necessarily cis, this configuration is preferred when X2 represents two monodentate ligands.
R1,when other than hydrogen, is typically a methyl or isopropyl group. Substituents R, are typically located at the ring 4 or 5 position and the nitro group is preferably located at the 2 position in the imidazole ring.
R2 and R3 both typically represent hydrogen although compounds in which one or both of R2 and R2 represent an alkyl group are also of interest.
It is generally preferred that the side chain comprises no more than five carbons so that a+b+c+d+e5. The presence of an hydroxyl group on the beta carbon with respect to the imidazole ring is also generally preferred, in which case when b is 1 or 2, a is usually 1. Side chains of particular interest include the following, (Im represents the imidazole ring)::- lm-CH2CH2NH2 (a=1, b=O, c=l, d=O, e=O); Im-CH2CHOHCH2NH2 (a=1, b=1 , c=i, d=O, e=O); lm-CH2CHOH(CH2)2NH2 (a=1, b=1, c=2, d=O, e=O); lm-CH2CHOH(CH2)3NH2 (a=1, b=1, c=2, d=O, e=l); Im-(CH2)2CHOH CH2NH2
(a=2, b=1, c=2, d=O, e=O); Im-CH2C HOHCHOH CH2NH2
(a=1, b=1, c=O, d=1, e=1).
Compounds I may be produced, in accordance with a further aspect of the present invention by reaction of a compound of formula II preferably in the form of an acid addition salt e.g. a hydrochloride, with a platinum compound of formula Ill:-
M2PtX4 Ill wherein M represents an alkali metal e.g. potassium, X typically represents chlorine.
When the compound II is in the form of an acid addition salt, the reaction is usually conducted in the presence of a base such as sodium hydroxide so that the free amine is liberated for reaction with the compound Ill.
Intermediate compounds II are also included within the scope of the present invention, provided that R2 and R3 both represent hydrogen.
Compounds of formula II, particularly those in which R2 and R3 both represent hydrogen, may be prepared in accordance with a further aspect of the present invention by treatment of a phthalimide compound of formula IV with hydrazine, typically in hydrated form, suitably in a protic solvent such as an alcohol.
Intermediate compounds of formula II wherein one or both of R2 and R3 represent alkyl groups may however be produced by following a method described in UK Patent Application No. 20031 54A.
Intermediate compounds IV are also included within the scope of the present invention and may be prepared, in accordance with a yet further aspect of the present invention, by reaction of a nitroimidazole of formula Vwith a compound of formula VI:
The reaction is usually conducted under basic conditions, in the presence for example of potassium carbonate and in a protic solvent, e.g. an alcohol.
Intermediate compounds VI are also included within the scope of the present invention.
Certain compounds IIA of formula II may also be produced in accordance with a further aspect of the present invention by reaction of a compound of formula VII with ammonia, preferably in aqueous solution
Such compounds IIA may, of course, be readily converted into acid addition salts thereof by treatment with acids.
Compounds I are useful in increasing the sensitivity of tumour cells to radiation in radiotherapy and also in potentiating or enhancing damage to tumours by chemotherapeutic agents.
The compounds may be formulated in a manner appropriate to the treatment for which they are to be used by bringing them into association with pharmaceutically compatible carriers or diluents. The compounds may be included in a dosage form such as a tablet or capsule, for example a capsule comprising known formulation components such as one or more of those described in Example A of UK
Patent Application No. 20031 54A. The compound may also be formulated for intravenous administration e.g. in a saline drip solution.
When employed as a radiation sensitizing agent, in accordance with a further aspect of the present invention, a compound I is administered to a patient having a radiation sensitive cancer prior to irradiation of said cancer.
A compound I may, however, in a yet further aspect of the present invention be employed for chemopotentiation of a chemotherapeutic agent by administration of the compound to a patient having a localised or metastatic cancer. Administration of a compound I is generally carried out prior to or simultaneously with administration of the chemotherapeutic agent, for example melphlan, cyclophosphamide or 5-fluorouracil or CCNU (1 -(2-chloroethyl)-3-cyclohexyl-1 -nitrosourca).
The invention is illustrated by the following Examples: Example 1 Dichloro-bis[2-(2-nitro-1 imidazolyl),ethylamine] platinum Ii 415 mg (1 mmol) potassium tetrachloroplatinate (II) is dissolved in 20 ml of water, filtered and added to a solution of 312 mg (2 mmol) of 2-(2-nitro-1 -imidazolyl)ethylamine. The mixture is stirred at room temperature for 6 hours and a yellow solid precipitates. This precipitate is filtered, washed sequentially with water, methanol and ether and then dried at room temperature in vacuo for 1 0-20 hours to give the product, yield 417 mg (72%).
Example 2
Dichloro-bis[3-(2-nitro-1 -im idazolyl)-2-hydroxypropylamine] platinum (it ) (a1) N-[3-(2-Nitrn-1 -imidazolyl)-2-hydroxypropyl]phthalimide
A mixture of 3.39 g (30 mmol) of 2-nitroimidazole, 6.70 g (33 mmol) of N-(2,3epoxypropyl)phthalimide, 0.50 g of anhydrous potassium carbonate and 100 ml of ethanol is heated under reflux for 5-6 hours. After 1-2 hours a new, crystalline solid begins to form. The hot mixture is filtered and the solid is washed with water, boiling ethanol and dried to yield 5.61 g (59%) of N-[3-(2 nitro-1-imidazolyl)-2-hydroxypropyl]phthalimide as a yellow coloured crystalline solid, m.p. 212- 2140C.
(a2) N-[3-(2-Nitro-1 -imidazolyl)-2-hydroxypropyl] phthalimide (Alternative method) A mixture of 5.10 g (30 mmol) 1-(2,3-epoxypropyl)-2-nitroimidazole, 4.41 g (30 mmol) phthalimide, 0.50 g anhydrous potassium carbonate and 100 ml ethanol is heated under reflux for 4 1 6 hours. During refluxing a new, crystalline solid begins to form. The hot mixture is filtered and the solid is washed sequentially with water, and boiling ethanol and dried to give 5.89 g (62%) of N-[3-(2 nitro-1-imidazolyl)-2-hydroxypropyl]phthalimide as a yellow coloured crystalline solid m.p. 212- 2140C.
(b) 3-(2-Nitro-1 -imidazolyl )-2-hydroxypropylamine hydrochloride
A mixture of 15.08 g (50 mmol) N-[3-(2-nitro-1 -imidazole)-2-hydropropyl]phthalimide, 2.76 g (55 mmol) hydrazine hydrate (99100%) and 200 ml ethanol is heated under reflux for 1-2 hours.
After cooling, 50 ml of water is added and ethanol is removed by concentration under reduced pressure. The mixture is warmed to 50"C for 1 hour with 100 ml of 5NHCI and allowed to cool to room temperature over 30 minutes. The phthalhydrazide is removed by filtration. The filtrate is concentrated under reduced pressure and the residue is redissolved in the minimum quantity of hot water, treated with decolourising charcoal, filtered and allowed to crystallise to yield 7.83 g (70%) 3-(2-nitro-1 imidazoiyl)-2-hydroxypropylamine hydrochloride in the form of a white coloured crystalline solid melting point 21 1-2130C.
(c) Dichloro-bis[3-(2-nitro-1 imidazolyl)-2-hydroxypropylamine] platinum (II) 41 5 mg (1 mmol) K2PtCI4 and 4.46 mg (2 mmol) 3-(2-nitro-1 -imidazolyl)-2-hydroxypropylamine hydrochloride are dissolved in the minimum amount of water, filtered and IN NaOH (2 ml) is added to the solution which is stirred at room temperature for 4-20 hours when a yellow precipitate forms.
Further material is obtained on allowing the filtrate to stand. The product is filtered off, washed sequentially with water, methanol and ether and dried at room temperature in vacuum for 10-20 hours to yield 5.08 mg (79%) product.
Example 3 Dichloro-bis[4-(2-nitro-1-imidazolyl)-3-hydroxybutylamine] platinum (II) (a) N-(3-butenyl)phthalimide
A mixture of 37.0 g (0.2 mol) potassium phthalimide, 29.80 g (0.22 mol) 4-bromo-1-butene and 1 50 ml N,N-dimethylformamide is heated at 1 00-1 200C for 1.5 hours. The precipitated potassium bromide is filtered off, and the excess 4-bromo-1 -butene and N,N-dimethylformamide are removed under reduced pressure. The residue is taken up in chloroform/water and chloroform extract is washed sequentially with 0.1 N sodium hydroxide, water and then dried. Filtration and concentration gives a yellow-brown oil which is extracted with hot petroleum ether b.p. 60-800C and the insoluble material is removed. The resultant solution is concentrated and, from this, 23 g (57%) N-(3-butenyl)phthalimide, is obtained as a white crystalline solid m.p. 50-520C.
(b) N-(3,4-Epoxybutyl)phthalimide
To a solution of 20.10 g (0.10 mol) N-(3-butenyl)phthalimide and 0.50 g 3-tert-butyl-4-hydroxy5-methylphenyl sulphide in 200 ml 1,2-dichloroethane is added 22.36 g (0.13 mol) mchloroperoxybenzoic acid in 100 ml 1,2-dichloroethane during a period of 4 hours at OOC. After the addition the reaction mixture is stirred at room temperature for 1 0-20 hours and then refluxed for 2 hours. The mixture is washed sequentially with saturated sodium bicarbonate solution, 1 0% sodium carbonate solution, water and then dried. The 1,2-dichloroethane was removed under reduced pressure and the resulting residue is crystallised from ether/petroleum ether to give 1 7.06 g (79%) N (3,4-epoxybutyl)phthalimide in the form of a white solid m.p. 83-850C.
(c) N-[4-(2-N itro-1 -imidazolyl)-3-hydroxybutyl]phthalimide In a manner analogous to that described in Example 2(at) there is obtained by reaction of the product from the latter procedure (b) N-[4-(2-nitro-1 -imidazolyl)-3-hydroxybutyl]phthalimide in the form of a yellow coloured solid of melting point 220--2220C; yield (64%).
(d) 4-(2-Nitro-1-imidazolyl)-3-hydroxybutylamine hydrochloride monohydrate
In a manner analogous to that described in Example 2(b) there is obtained by reaction of the product from the latter procedure (c), after crystallisation from water/ethanol, 4-(2-nitro-1 -imidazolyl)3-hydroxybutylamine hydrochloride in the form of a white crystalline solid of melting point 1 84- 1 860C; yield (78%).
(e) Dichloro-bis[4-(2-nitro-l -imidazolyl)-3-hydroxybutylamine] platinum (II).
In a manner analogous to that described in Example 2(c) there is obtained by reaction of the product from the latter procedure (d) dichloro-bis[4-(2-nitro-1 -imidazolyl)-3
hydroxybutylamine] platinum (II) in the form of a yellow crystalline solid, yield 586 mg (88%).
Example 4 Dichloro-bis[5-(2-nitro-1-imidazolyl)-4-hydroxypentylamine] platinum (II) (a) N-(4-Pentenyl)phthalimide
In a manner analogous to that described in Example 3(a) there is obtained from 5-bromo-1 pentene after crystallisation from petroleum ether b.p. 60--800C, N-(4-pentenyl)phthalimide in the form of a white crystalline solid, melting point 35--379C, yield 29.04 g (67%).
(b) N-(4,5-Epoxypentyl)phthalimide
In a manner analogous to that described in Example 3(b) there is obtained from the product of the latter procedure (a) after crystallisation from ether/petroleum ether b.p. 60-800C at a low temperature, N-(4,5-epoxypentyl)phthalimide in the form of a colourless oil (at room temperature), yield 75%.
(c) N-[5-(2-Nitro-1 -i midazolyl)-4-hydroxypentyl] phthal imide
3.39 g (30 mmol) 2-nitroimidazoie are heated with 6.93 g (30 mmol) N-(4,5epoxypentyl)phthalimide and 0.50'g anhydrous potassium carbonate in 100 ml of ethanol for 5 hours.
The potassium carbonate is removed by filtration and the filtrate is concentrated and allowed to cool to give N-[5-(2-nitro-1 -imidazolyl)-4-hydroxypentyl]phthalimide which is recrystallised from ethanol as a yellow crystalline solid, melting point 150--1520C; yield 5.78 g (56%).
(d) 5-(2-N itro-1 -imidazolyl)-4-hydroxypentylamine hydrochloride monohydrate
In a manner analogous to that described in Example 2(b) there is obtained, from the product of the latter procedure (c) after crystallisation from aqueous ethanol 90%, 5-(2-nitro-1-imidazolyl)-4- hydroxypentylamine hydrochloride in the form of a white crystalline solid, melting point 146-1 470 C; yield 74%.
(e) Dichloro-bis[5-(2-nitro-1 -imidazolyl)-4-hydroxypentylamine] platinum (II)
In a manner analogous to that described in Example 2(c) there is obtained from the product of the
latter procedure (d) dichloro-bis[5-(2-nitro-1 -imidazolyl)-4-hydrnxypentylamine] platinum (11) in the form of a brown sticky solid which changes to a yellow coloured solid on drying and grinding; yield 584
mg (80%).
Example 5
Dichloro-bis[4-(2-nitro-1 -imidazolyl)-2- hydroxybutylamine] platinum (II) (a) I -(2-N itro-I -imidazolyl )-3-butene
A mixture of 11.3 g (0.10 mol) 2-nitroimidazole, 5.4 g (0.10 mol) sodium methoxide, 0.200 g sodium iodide, 13.5 g (0.10 mol) 4-bromo-1-butene, 100 ml N,N-dimethylformamide and 50 ml methanol is heated at 1 10--1 120C for 4 hours. The reaction mixture is raised to the required temperature by allowing the methanol to evaporate. The precipitated sodium bromide is filtered off and
the solvents are removed under reduced pressure to give a brown oil, which is taken up in
chloroform/lN sodium hydroxide.The chloroform extract is washed with water, dried, filtered and
concentrated to give a brown oily residue, from which 13.36 g (80%) 1 -(2-nitro-1 -imidazolyl)-3- butene is obtained in the form of a yellow coloured oil after carrying out column chromotography using
silica gel as adsorbent.
(b) 1 -(2-Nitro-1 -i midazolyl)-3,4-epoxybutane In a manner analogous to that described in Example 3(b) there is obtained, from the product of the latter procedure (a) after column chromatography through silica gel column, 1 -(2-nitro-1 - imidazolyl)-3,4-epoxybutane in the form of a yellow coloured oil; yield 88%.
(c) N-[4-(2-Nitro-1 -i midazolyl)-2-hydroxybutyl] phthalimide
In a manner analogous to that described in Example 2(a2) there is obtained N-[4-(2-nitro-1imidazolyl)-2-hydroxybutyl]phthalimide in the form of a yellow crystalline solid, melting point 1 89- 191 C; yield (57%).
(d) 4-(2-Nitro-1 -imidazolyl)-2-hydroxybutylamine hydrochloride
In a manner analogous to that described in Example 2(b) there is obtained 4-(2-nitro-1imidazolyl)-2-hydroxybutylamine hydrochloride in the form of a pale yellow gum which is homogeneous; thin-layer chromatography indicates the yield is 78%.
(e) Dichloro-bis[4-(2-nitro-1-imidazolyl)-2-hydroxybutylamine] platinum (II)
In a manner analogous to that described in Example 2(c) there is obtained dichloro-bis[4-(2-nitro 1-imidazolyl)-2-hydroxybutylamine] platinum (II) in the form of a yellow crystalline solid, yield 68%.
Example 6 Dichloro-bis[4-(2-nitro-I -imidazolyl)-2,3-dihydroxybutylamine] platinum (II)
Method A
Phthalimide is treated with a mixture of 3,4 epoxy but-1-ene, ethanol and potassium carbonate to yield N-(2-hydroxy-3-butenyl)phthalimide which is treated with m-chloroperbenzoic acid in dichloroethane to yield N-(2-hydroxy-3,4 epoxybutyl)phthalimide. The latter compound is treated with a mixture of ethanol and potassium carbonate to yield 4-(2-nitro-1 -imidazolyl)-2,3-dihydroxybutyl phthalimide which on treatment with a mixture of hydrazine and 4N hydrochloric acid gives 3-(2-nitro1 -imidazolyl)-2,3-dihydroxybutylamine hydrochloride. Reaction of the latter compound with potassium chloroplatinate yields the platinum complex.
Method B
2-Nitroimidazole is reacted with a mixture of 3,4-epoxybut-1 -ene ethanol and potassium carbonate to yield 1 -(2-nitroimidazolyl)-2-hydroxy-3-butene, which on oxidation by mchloroperbenzoic acid in dichloroethane, yields 1-(2-nitroimidazolyl)-2-hydroxy-3,4-epoxybutane. The latter compounds on reaction with a mixture of phthalimide, ethanol and potassium carbonate yields 4 (2-nitroimidazolyl)-2,3-dihydroxybutyl phthalimide which is converted to the required platinum complex by following Method A.
Examples 7-9 The following Examples illustrate the enhancement ratios obtained by the use of the compounds of Examples 1, 2 and 4 prior to irradiation of hypoxic U79 cells. The results are set out in the Table together with comparison results using the complex 'FLAP'.
table
Enhancement Enhancement ratio at ratio at 0.1 mM maximum Ex. No. Structure dosage cone tested 1 1 ctc,NC rc1 1.67 2.1 3a jPivas jHO2~ 2 [cN\\ ~ ~ 1.36 1.53b -i ,CHoYC,ErH CI1 N4F 4 1.30 1.41b ;LC1i0 & ci(o\\(c{{)ati;i 0 2 1.41b NO, 1.
Comparison FLAP 1.10 1.1 6b a: Toxic concentration of 0.25 mM (survival level 40% of control)
b: 0.25 mM non-toxic concentration
Claims (48)
1. A compound of formula (I)
in which:
R, represents hydrogen or C1-C6 alkyl,
R2 and R3 each independently represent hydrogen or C1-C6 alkyl,
X represents a pharmaceutically acceptable ligand incapable of co-ordinating to platinum more strongly than does nitrogen of the moiety-NR2R3 ais 1 or 2 bis0,1 or2
cis 1 or2 dis0,1 or2 tis0, 1 or2 provided that b+d is no greater than 2 and when d is greater than 0, e is greater than 0.
2. A compound according to claim 1 in which the pharmaceutical acceptable ligands X are identical or different monodentate ligands.
3. A compound according claim 2 in which both ligands X represent halogen.
4. A compound according to claim 3 in which both ligands X represent chlorine.
5. A compound according to any one of claims 2 to 4 which has a cis configuration.
6. A compound according to claim 1 in which X2 represent a bidentate ligand.
7. A compound according to claim 6 in which the bidentate ligand has the formula O.CO.CRaRbCO.O, in which Ra and Rb, which may be identical or different, each represent hydrogen or an alkyl, aryl, aralkyl, alkenyl, cycloalkyl or cycloalkenyl group or CRaRb represents a cycloalkyl or cycloalkenyl group.
8. A compound according to any one of the preceding claims in which R1 is a methyl or isopropyl group.
9. A compound according to any one of the preceding claims in which R, is located at the 4- or 5position and the nitro group is located at the 2-position in the imidazole ring.
1 0. A compound according to any one of the preceding claims in which R2 and R3 both represent hydrogen.
11. A compound according to any one of the preceding claims in which a+b+c+d+e5.
12. A compound according to any one of the preceding claims in which b is 1 or 2 and a is 1.
13. Dichloro-bis[2-(2-nitro-1 -imidazolyl) ethylamine] platinum II.
14. Dichloro-bis[3-(2-nitro-1 imidazolyl)-2-hydroxypropylaminei platinum II.
1 5. Dichloro-bis[4-(2-nitro-l -imidazolyl)-3-hydroxybutylamine] platinum 11.
1 6. Dichloro-bis[5-(2-nitro- 1 -imidazolyl)-4.-hydrnxypentylaminej platinum II.
1 7. Dichloro-bis[4-(2-nitro-1 -imidazolyl)-2-hydroxybutylaminel platinum II.
1 8. Dichloro-bis[4-(2-nitro-1 -imidazolyl)-2,3-dihydrnxybutylamine] platinum II.
19. A process for the preparation of a compound of formula (I) as defined in claim 1, which process comprises reacting a compound of formula (II)
in which R1, R2, R3, a, b, c, d and e are as defined in claim 1, or an acid addition salt thereof, with a platinum compound of formula (III): M2PtX4 (III) wherein M represents an alkali metal and X is as defined in claim 1.
20. A process according to claim 19 in which the compound of formula (II) is in the form of its hydrochloride.
21. A process for the preparation of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in any one of Examples 1 to 6.
22. A formulation comprising a compound of formula (I) as defined in claim 1 in association with a pharmaceutically acceptable carrier or diluent.
23. A method of increasing the sensitivity to radiation of tumor cells of a patient having a radiation-sensitive cancer, which method comprises administering to the patient a compound of formula (I) as defined in claim 1 prior to irradiation of said cancer.
24. Products containing a compound of formula (I) as defined in claim 1 and a chemotherapeutic agent as a combined preparation for simultaneous or separate use or for sequential use in which the compound of formula (I) is administered prior to the chemotherapeutic agent in the treatment of a localised or metastatic cancer.
25. Products according to claim 24 in which the chemotherapeutic agent is melphlan, cyclophosphamide, 5-fluorouracil or 1 -(2-chloroethyl)-3-cyciohexyl-l -nitrosourea.
26. A compound of formula (II) as defined in claim 19 in which both R2 and R3 represent hydrogen and acid addition salts thereof.
27. 2-(2-Nitro-1 -imidazolyl)ethylamine
28. 3-(2-Nitro-1 -imidazolyl)-2-hydroxypropylamine hydrochloride.
29. 4-(2-Nitro- 1 1 -i m idazolyl)-3-hydroxybutyla mi ne hydrochloride monohydrate.
30. 5-(2-Nitro-l -imidazolyl)-4-hydroxypentylamine hydrochloride monohydrate.
31.4-(2-Nitro-1 -imidazolyl)-2-hydroxybutylamine hydrochloride.
32. 3-(2-Nitro- 1 -imidazolyl)-2,3-dihydroxybutylamine hydrochloride.
33. A process for the preparation of a compound of formula (II) as defined in claim 17 in which R2 and R3 both represent hydrogen, or an acid addition salt thereof, which process comprises of treating a phthalimide of formula (IV)
in which R1, a, b, c, d and e are as defined in claim 1 , with hydrazine and if desired, converting the resulting compound of formula (II) into an acid addition salt thereof.
34. A process for the preparation of a compound of formula (IIA):
in which R1, a and b are as defined in claim 1, or an acid addition salt thereof, which process comprises reacting a compound of formula (VII):
in which R1, a and b are as defined in claim 1, with ammonia.
35. A process for the preparation of a compound of formula (II) as defined in claim 19 in which R2 and R3 both represent hydrogen or an acid addition salt thereof, said process being substantially as hereinbefore described in any one of Examples 2 to 6.
36. A compound of formula (IV) as defined in claim 33.
37. N-[3-(2-Nitro-1-imidazolyl)-2-hydroxypropyl]phthalimide.
38. N-[4-(2-Nitro-1 -imidazolyl)-3-hydroxybutyl]phthalimide.
39. N-[5-(2-Nitro- 1 -im idazolyl)-4-hyd roxypentyl]phthalimide.
40. N-[4-(2-Nitro- 1 -imidazolyl)-2-hydroxybutyl]phthali mide.
41. 4-(2-Nitroimidazolyl)-2,3-dihydroxybutyl phthalimide.
42. A process for the preparation of a compound of formula (IV) as defined in claim 33 in which b is 1, which process comprises reacting a nitroimidazole of formula (V):
with the compound of formula (VI):
in which c, d and e are as defined in claim 1.
43. A process for the preparation of a compound of formula (IV) as defined in claim 33 in which b is 1, said process being substantially as hereinbefore described in any one of Examples 2 to 6.
44. A compound of formula (VI) as defined in claim 1 8.
45. N-(2,3-Epoxypropyl)phthalimide.
46. N-(3,4-Epoxybutyl)phthalimide.
47. N-(4,5-Epoxypentyl)phthalimide.
48. N-(2-Hydroxy-3,4-epoxybutyl)phthalimide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08331035A GB2131020B (en) | 1982-11-25 | 1983-11-21 | Improvements relating to compounds useful in radiotherapy or chemotherapy |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8233686 | 1982-11-25 | ||
| GB08331035A GB2131020B (en) | 1982-11-25 | 1983-11-21 | Improvements relating to compounds useful in radiotherapy or chemotherapy |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8331035D0 GB8331035D0 (en) | 1983-12-29 |
| GB2131020A true GB2131020A (en) | 1984-06-13 |
| GB2131020B GB2131020B (en) | 1986-10-01 |
Family
ID=26284500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08331035A Expired GB2131020B (en) | 1982-11-25 | 1983-11-21 | Improvements relating to compounds useful in radiotherapy or chemotherapy |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2131020B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4550169A (en) * | 1983-11-21 | 1985-10-29 | American Cyanamid Company | Platinum chelates of 2-hydrazino-azoles |
| EP0287317A2 (en) * | 1987-04-13 | 1988-10-19 | The British Columbia Cancer Foundation | Platinum complexes with one radiosensitizing ligand |
| GB2209161A (en) * | 1987-06-05 | 1989-05-04 | Univ Beijing Polytechnic | Cis-platinum-diamine complexes, anti-tumorous compositions containing them, and methods for their preparation |
| EP0319329A2 (en) * | 1987-12-04 | 1989-06-07 | Btg International Limited | Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment |
| US5602142A (en) * | 1994-12-21 | 1997-02-11 | Evanston Hospital Corporation | DNA-affinic hypoxia selective cytotoxins |
| EP0830357A1 (en) * | 1995-03-31 | 1998-03-25 | Florida State University | Radiosensitizing diamines and their pharmaceutical preparations |
| DE10141528A1 (en) * | 2001-08-24 | 2003-03-13 | Faustus Forschungs Cie | Platinum (II) and platinum (IV) complexes and their use |
| US7829555B1 (en) | 1997-02-11 | 2010-11-09 | The University Of Manchester | Drug targeting |
| WO2022084325A1 (en) * | 2020-10-20 | 2022-04-28 | Institut Curie | Metallic trans-(n-heterocyclic carbene)-amine-platinum complexes and uses thereof for treating cancer |
-
1983
- 1983-11-21 GB GB08331035A patent/GB2131020B/en not_active Expired
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4550169A (en) * | 1983-11-21 | 1985-10-29 | American Cyanamid Company | Platinum chelates of 2-hydrazino-azoles |
| EP0287317A2 (en) * | 1987-04-13 | 1988-10-19 | The British Columbia Cancer Foundation | Platinum complexes with one radiosensitizing ligand |
| EP0287317A3 (en) * | 1987-04-13 | 1989-02-08 | The British Columbia Cancer Foundation | Platinum complexes with one radiosensitizing ligand |
| GB2209161A (en) * | 1987-06-05 | 1989-05-04 | Univ Beijing Polytechnic | Cis-platinum-diamine complexes, anti-tumorous compositions containing them, and methods for their preparation |
| GB2209161B (en) * | 1987-06-05 | 1991-10-02 | Univ Beijing Polytechnic | Cis-platinum-diamine complexes, anti-tumorous compositions containing them, and methods for their preparation |
| EP0319329A2 (en) * | 1987-12-04 | 1989-06-07 | Btg International Limited | Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment |
| EP0319329A3 (en) * | 1987-12-04 | 1990-03-07 | National Research Development Corporation | Nitro-substituted aromatic or hetero-aromatic compounds nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment for use in cancer treatment |
| US5098921A (en) * | 1987-12-04 | 1992-03-24 | National Research Development Corporation | Nitro-substituted aromatic or hetero-aromatic compounds for use in cancer treatment |
| US5602142A (en) * | 1994-12-21 | 1997-02-11 | Evanston Hospital Corporation | DNA-affinic hypoxia selective cytotoxins |
| US5958947A (en) * | 1994-12-21 | 1999-09-28 | Evanston Hospital | DNA-affinic hypoxia selective cytotoxins |
| EP0830357A1 (en) * | 1995-03-31 | 1998-03-25 | Florida State University | Radiosensitizing diamines and their pharmaceutical preparations |
| EP0830357A4 (en) * | 1995-03-31 | 2000-01-19 | Univ Florida State | Radiosensitizing diamines and their pharmaceutical preparations |
| US7829555B1 (en) | 1997-02-11 | 2010-11-09 | The University Of Manchester | Drug targeting |
| DE10141528A1 (en) * | 2001-08-24 | 2003-03-13 | Faustus Forschungs Cie | Platinum (II) and platinum (IV) complexes and their use |
| DE10141528B4 (en) * | 2001-08-24 | 2006-08-10 | Faustus Forschungs Cie. Translational Cancer Research Gmbh | Platinum (II) and platinum (IV) complexes and their use |
| WO2022084325A1 (en) * | 2020-10-20 | 2022-04-28 | Institut Curie | Metallic trans-(n-heterocyclic carbene)-amine-platinum complexes and uses thereof for treating cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2131020B (en) | 1986-10-01 |
| GB8331035D0 (en) | 1983-12-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19921121 |